1H-Pyrrolo[2,3-b]pyridine Analogs as PLK4 Inhibitors

Abstract

Polo-like kinase 4 (PLK4), a serine/threonine kinase, is a major regulator of centriole replication during the cell cycle. Extensive studies have demonstrated that abnormal expression of PLK4 is associated with several cancers in humans. Therefore, PLK4 is a potential therapeutic target for the treatment of cancer. To identify potential PLK4 inhibitors, an in-house kinase library was screened, revealing that several serum/glucocorticoid-regulated kinase 1 (SGK1) inhibitors have PLK4 inhibitory activity. Structural analysis highlighted that the 5-methylenethiazolidine-2,4-dione moiety at the 3-position of 1H-pyrrolo[2,3-b]pyridine played a crucial role in kinase selectivity. Docking studies using PLK4 crystal structures (DFG-in and DFG-out conformations) demonstrated that distinct binding orientations are influenced by steric and electronic factors. Further structure-activity relationship studies revealed that the presence of a terminal amino group was critical for the inhibition of SGK1 but it had minimal impact on PLK4 activity. The replacement of thiazolidine-2,4dione with 2-(hydroxyimino)thiazolidin-4-one shifted the selectivity towards PLK4, primarily through enhanced hydrogen bonding. These findings provide valuable insights into the design of selective PLK4 inhibitors and their structural determinants.